The longterm goal of these studies is to understand the physiological consequences of global cerebral hypoxia, and how failure of the normal homeostatic mechanisms contributes to cerebral disease. The human brain has a high energy demand and a low tolerance for interruptions of oxygen availability. Our overall hypothesis is that any lowering of tissue oxygenation (PtO2) leads to a progressive deterioration of the health of the brain, rather than impairment only when PtO2 reaches very low threshold levels. If true, this idea has implications for the management and treatment of a wide range of conditions causing brain injury that have a hypoxic component to them. The critical factor that determines injury in this scenario is the degree to which tissue oxygenation decreases. Testing this overall hypothesis in humans is chalenging; the normal physiological responses are altered once hypoxic injury has occurred, thus we need a physiological model of tissue hypoxia without concomitant disease. During our recent studies investigating cerebral acclimatization to high altitude in human subjects, we found that Cerebral O2 metabolism (CMRO2) increases during hypoxia despite reduced O2 availability. Since tisue PtO2 is directly impacted by cerebral blood flow (CBF) (supplying O2) and CMRO2 (removing O2), this paradoxical mismatch of O2 supply and demand has the potential to manipulate PtO2 and thus to test our overall hypothesis of the central role of PtO2 in determining cerebral vulnerability to hypoxia. Our goal in this project is o use novel MRI techniques to measure CBF, CMRO2 and PtO2 to test the influence of PtO2 on cerebral susceptibility to hypoxia in human subjects. Our first Specific Aim is to examine the role of arterial PaCO2 to explain the increase of CMRO2 during acute hypoxic exposure. We wil test how high, normal and low CO2 during normoxic and hypoxic conditions impact CMRO2. Our second Specific Aim is to test if subjects vulnerable to hypoxic cerebral ilnes (manifest as susceptibility to acute mountain sickness - AMS) show a greater drop in tissue PtO2 on exposure to hypoxia conditions than AMS-resistant subjects. This series of studies will test our model of paradoxical CMRO2 response to hypoxia as a means to influence tissue oxygenation, and from this determine the importance of high tissue oxygenation for conferring resistance to cerebral hypoxic disease PUBLIC HEALTH RELEVANCE: The brain has a high energy demand and a low tolerance for interruptions of oxygen availability. In this proposal we use novel MRI techniques to measure cerebral blood flow (CBF) oxygen metabolism (CMRO2) and tissue oxygenation (PtO2) to test our hypothesis that maintaining a high PtO2 is necessary for the health of the brain. If true, this idea has implications for the management and treatment of a wide range of conditions causing brain injury that have a hypoxic component to them.